Acid anhydrides as rate controlling agent for the erosion of polymers which latter polymers have beneficial substances dispersed throughout their matrix or where the polymer matrix surrounds the beneficial substance

ABSTRACT

The invention relates to the use of an acid anhydride incorporated as a latentiated catalyst in poly(ortho ester) and other polymers such that upon exposure to aqueous environments the acid anhydride generates the corresponding acid which catalyzes the matrix erosion. The releasing rate of a loaded drug substance incorporated into or surrounded by the poly(ortho ester) or other polymers can be controlled in that the drug is released as the poly(ortho ester)s or other polymer is eroded by action of the acid anhydride incorporated therein.

BACKGROUND OF THE INVENTION

There has been a long need in the field of drug delivery devices to havea drug released in the human body at the place where it is mosttherapeutically effective and to have said drug released in the body ina controlled manner over a long period of time.

There is art showing that poly(ortho ester)s and other polymers can beused as a matrix for drug release; however, there is no description inany of this art of the use of acid anhydrides as catalysts to promotethe polymer erosion in a controlled fashion.

Also, the release of norethindrone from poly(ortho ester)s slabs hasbeen described in the prior art. However, in this system a water-solublesalt such as sodium chloride and the like was incorporated into thepolymer and the proposed mechanism for drug release in this case wasosmotic imbibing of water, causing the matrix to swell and burst. Thedrug release was not controlled by polymer erosion but by a swellingprocess.

SUMMARY AND DESCRIPTION OF THE INVENTION

This invention relates to the use of acid anhydrides as rate-controllingagents for the erosion of poly(ortho ester)s and other polymers to whichtherapeutically effective drug substance(s) or other beneficialsubstances (hereafter collectively referred to as biologically activeagents) have been added are surrounded by such polymers and anhydridemixtures so that as said polymer is eroded, the drug or other substanceis released in a controlled manner.

It has been noted that poly (ortho ester)s and some other polymerlinkeages herein described are sensitive toward acids but relativelystable at neutral or basic pH. Thus, an acid anhydride which isincorporated as a latentiated catalyst in the polymer matrix wouldgenerate a corresponding acid upon exposure to aqueous environments andsubsequently catalyze the matrix erosion. If, in addition, apharmaceutical or therapeutic agent or drug is incorporated in thematrix of the polymer, it can be seen that the drug can be relesed at apredictable rate from the polymer matrix as the polymer matrix is erodedby action of the acid generated from the incorporated acid anhydride.Also the polymer/acid anhydride matrix could surround the drug orbeneficial substance whereby the drug or substance will be released whenthe polymer/acid hydride matrix coating is erroded. The proposedmechanism for breakdown and erosion of the polymer [here a poly(orthoester) is shown] can be shown by the following equations where R' is asdefined further along. ##STR1##

The rate of polymer matrix erosion and subsequently the rate of releaseof any drug substance or pharmaceutically therapeutic substanceincorporated into or surrounded by the matrix can be controlled bychoosing the proper acid anhydride or combination of acid anhydrides.This can be done and the rate of erosion can be correlated with the pKaof the corresponding acid. Also, the concentration of the acidanhydride(s) incorporated into the polymer matrix will control the rateof erosion of the polymer matrix and subsequently the rate of release ofthe drug substance incorported therein. We have observed a linearrelationship between the concentration of the acid anhydrideincorporated and the rate of release of the drug substance and rate oferosion of the polymer when the drug or beneficial substance isincorporated in the polymer/acid anhydride matrix.

When the drug or beneficial substance is surrounded or coated by thepolymer/acid anhydride matrix, the drug or beneficial substance can bedischarged when the matrix erodes in a predictable time frame.

In a more detailed description of the invention, the following types ofpolymers can be used and also the following types of acid anhydrides canbe used. Also there is described the type of pharmaceuticals,therapeutic agents or drugs or beneficial substances which can beincorporated into or surrounded by the matrix of said polymer to bereleased by reaction of the acid anhydride to form the correspondingacid which upon exposure to aqueous environments subsequently catalyzesthe matrix erosion.

The polymers which can be used in our invention are all those describedin U.S. Pat. No. 4,304,767 to Heller and U.S. Pat. No. 4,093,709 to Choiand Heller and others described below.

Examples of the polymers covered in these two patents and which areapplicable to our invention are:

1. Polymers of di(or higher functionality) keteneacetals and polyolswhich have a repeating mer unit of ##STR2## wherein n is an integersubstantially greater than 10; wherein R₁ and R₂ are hydrogen or thesame or different essentially hydrocarbon groups and may be separategroups or may form parts of a cyclic group; R is a quadrivalent organicgrouping; R₃ and R₄ are hydrogen or the same or different essentiallyhydrocarbon groups and may be separate groups or may form parts of acyclic group; R₅ is an essentially hydrocarbon group which is theresidue of a polyol R₅ (OH)_(a) wherein a is an integer equal to two ormore, such polyol being a single molecular species or a mixture ofmolecular species; and wherein such linear chain may be crosslinked withother similar chains, and wherein R may be a single quadrivalent radicalattached to all the interim acetal forming oxygen atoms, may be a spirostructure, may be an open chain aliphatic group, or may contain acarbocyclic group. Additionally, R₅ may contain some mer units that arealkylene or contain a carbocyclic group. Also included are polymershaving the repeat units ##STR3## wherein n is an integer substantiallygreater than 10; wherein R₁, R₂, R₃ and R₄ are the same or differentessentially hydrocarbon groups, R₁ and R₂ being separate groups or partsof a cyclic group and R₃ and R₄ being separate groups or parts of acyclic group; R₅ is an essentially hydrocarbon group which is theresidue of a polyol R₅ (OH)_(a) wherein a is an integer equal to two ormore, such polyol being a single molecular species or a mixture ofmolecular species; R₆ is a valence bond or an essentially hydrocarbongroup; R₇ and R₈ are hydrogen or essentially hydrocarbon groups whichmay be separate groups or may form parts of a cyclic group; and whereinsuch linear chains may be crosslinked to similar chains are also part ofour invention. The group ##STR4## may be selected from the classicalkylene end groups containing a carbocyclic ring.

2. Poly(orthoester) or polyorthocarbonate polymers of the formula:##STR5## wherein R₁ is a multivalent hydrocarbon radical, R₂ and R₃ arehydrocarbon radicals with at least one of R₂ and R₃ are hydrocabronradicals with at least one of R₂ or R₃ bonded to the dioxycarbon throughan oxygen linkage and n is a repeated mer unit.

3. Other broad classes of polymers to which this invention is applicableare those polymers with backbone functionalities which are sensitive toacid. Examples of these include polyacetals and polyketals of theformula: ##STR6## wherein R', R"=H, alkyl or aryl

R=alkylene, arylene and

n is a repeating mer unit. ##STR7## wherein R', R"=H, alkyl or aryl and

n=is a repeating mer unit.

and

4. Polyesters such as polylactate, polyglycolate, polycaprolactones andrandom co-polymers of the formulae: ##STR8## wherein n is a repeatingmer unit and R and R¹ are as defined in 3 above.

The type of acid anhydrides which can be used in the invention are shownbelow.

I. 1. Monobasic carboxylic: ##STR9## R, R' are hydrogen or saturated orunsaturated hydrocarbon radicals containing up to 50 carbon atomsincluding aliphatic and aromatic groupings.

2. Dibasic carboxylic anhydrides of the type

i. cyclic ##STR10## wherein R=(CH₂)_(n) where (n=2-4) and R' is asdefined in 1 above for the anhydrides.

ii. polymeric ##STR11## wherein n is 4 to 50 and m is a repeating merunit. 3. sulfonic and sulfenic anhydrides of the formula ##STR12##wherein R is as defined above in No. 1 for anhydrides and

n is 1 or 2.

4. mixed function anhydrides of the general formula ##STR13## wherein Rand R' are as defined in No. 1 for anhydrides above and

X is O or S.

5. Inorganic acid anhydrides such as polyphosphoric anhydride.

Specific examples of acid anhydrides which are described above and whichcan be incorporated into the polymer matrix are:

1. Aliphatic, monobasic: Acetic, propionic or butyric anhydride

2. Cyclic dibasic:

saturated: succinic, glutaric, methylsuccinic or adipic anhydrides

unsaturated: maleic or citraconic anhydrides

3. Aromatic: Benzoic anhydride

4. Aromatic dibasic: phthalic anhydride or polyterphthalic anhydride

5. Polymeric: polyadipic or polysebasic anhydride

6. Sulfonic: phenyl sulfonic or ##STR14## wherein n=1-2 or

7. Mixed function anhydrides such as o-sulfobenzoic or 3-sulfopropionicanhydride.

Suitable drugs (therapeutics) and beneficial substances (biologicallyactive agents) for incorporation into or to be surrounded by the polymermatrix to be used with this invention and to be released to an aqueousenvironment include without limitation, the following:

1. Protein drugs such as insulin;

2. Desensitizing agents such as ragweed pollen antigens, hay feverpollen antigens, dust antigen and milk antigen;

3. Vaccines such as smallpox, yellow fever, distemper, hog cholera, fowlpox, antivenom, scarlet fever, dyptheria toxoid, tetanus toxoid, pigeonpox, whooping cough, influenzae, rabies, mumps, measles, poliomyelitis,Newcastle disease, etc.;

4. Anti-infectives, such as antibiotics, including penicillin,tetracycline, chlortetracycline bacitracin, nystatin, streptomycin,neomycin, polymyxin, gramicidin, oxytetracycline, chloramphenicol, anderythromycin; sulfonamides, including sulfacetamide, sulfamethizole,sulfamethazine, sulfadiazine, sulfamerazine, and sulfisoxazole,cefoxitin; anti-virals including idoxuridine; and other anti-infectivesincluding nitrofurazone and sodium propionate;

5. Antiallergenics such as antazoline, methapyrilene, chlorpheniramine,pyrilamine and prophenpyridamine;

6. Steroidal anti-inflammatory agents such as hydrocortisone, cortisone,hydrocortisone acetate, dexamethasone, dexamethasone 21-phosphate,fluocinolone, triamcinolone, medrysone, prednisolone, prednisolone21-phosphate, and prednisolone acetate;

7. Decongestants such as phenylephrine, naphazoline, andtetrahydrazoline;

8. Miotics such as pilocarpine, eserine salicylate, carbachol,diisopropyl fluorophosphate, phospholine iodide, and demecarium bromide;

9. Anticholinergics such as atropine sulfate, cyclopentolate,homatropine, scopolamine, tropicamide, eucatropine, andhydroxyamphetamine;

10. Sympathomimetics such as epinephrine;

11. Sedatives and Hypnotics such as pentabarbital sodium, phenobarbital,secobarbital sodium, codeine, (α-bromoisovaleryl)urea, carbromal;

12. Psychic Energizers such as 3-(2-aminopropyl)indole acetate,3-(2-aminobutyl)indole acetate and amitriptyline;

13. Tranquilizers such as reserpine, chlorpromazine, thiopropazate andperphenazine;

14. Androgenic steroids such as methyltestosterone and fluorymesterone;

15. Estrogens such as estrone, 17 β-estradiol, ethinyl estradiol, anddiethyl stilbesterol;

16. Progestational agents such as progesterone, megestrol, melengestrol,chlormadinone, ethisterone, norethynodrel, 19-nor-progesterone,norethindrone, medroxyprogesterone and 17 β-hydroxy-progesterone;

17. Humoral agents such as the prostaglandins, for example PGE₁, PGE₂and PGF₂ ;

18. Antipyretics analgesics such as aspirin, sodium salicylate,salicylamide, and diflunisal;

19. Antispasmodics such as atropine, methantheline, papaverine, andmethscopolamine bromide;

20. Antimalarials such as the 4-aminoquinolines, 8-aminoquinolines,chloroquine, and pyrimethamine;

21. Antihistamines such as diphenhydramine, dimenhydrinate,tripelennamine, perphenazine, and chlorophenazine;

22. Cardioactive agents such as dibenzhydroflumethiazide, flumethiazide,hydrochlorothiazide chlorothiazide, and aminotrate;

23. Non-steroidal anti-inflammatory agents such as indomethacin andsulindac;

24. Antiparkinsonian agents such as L-dopa;

25. Antihypertensive agents such as methyldopa;

26. β-Adrenergic blocking agents such as propanolol and timolol;

27. Nutritional agents such as vitamins, essential amino acids andessential fats.

Other drugs having the same or different physiological activity as thoserecited above can be employed in drug-delivery systems within the scopeof the present invention.

Other benificent compounds which can be released in a controlled mannerover time can also be incorporated in the present invention. Theseinclude but are not limited to herbicides, pesticides, fertilizers,antifouling agents, biocides (germacides). One skilled in the art wouldrealize that any beneficial substances which are released to the aqueousatmosphere can be used in this invention.

Drugs or therapeutically beneficial substances can be in various forms,such as uncharged molecules, components of molecular complexes, ornonirritating, pharmacologically acceptable salts such as hydrochloride,hydrobromide, sulfate, phosphate, nitrate, borate, acetate, maleate,tartrate, salicylate, etc. For acidic drugs, salts of metals, amines, ororganic cations (e.g., quaternary ammonium) can be employed.Furthermore, simple derivatives of the drugs (such as ethers, esters,amides, etc.) which have desirable retention and release characteristicsbut which are easily hydrolyzed by body pH, enzymes, etc., can beemployed.

The amount of drug or beneficial substance incorporated into the polymermatrix will vary greatly depending on the particular drug, the desiredtherapeutic effect and the time span in which the polymer matrix iseroded to release the particular drug. Thus, there is no critical upperlimit on the amount of drug incorporated in the polymer matrix and thelower limit will also depend on the activity of the drug and the timespan for the erosion of the polymer and subsequently the drug release.Thus, it is not practical to define a range for the therapeuticallyeffective amount of drug to be incorporated in the novel polymermatrixes and acid anhydride combinations of the instant invention.

Generally, the amount of acid anhydride or anhydrides incorporated intothe polymer will be dependent upon the release duration of the drug orbeneficial substance, and the particular acid anhydride used but wouldgenerally be in the range of slightly more than 0% to a maximum of about25% of the polymer by weight.

Also in the case of the drug or other beneficial substance incorporatedinto the polymer/acid anhydride matrix as stated above, the amount ofdrug or beneficial substance will depend on the type of drug orsubstance for the condition being treated and can generally be up to 70%of the polymer/acid anhydride matrix by weight.

The drug or beneficial substance can be administered in various ways andshapes. For example, the polymer/acid anhydride/drug or beneficialsubstance can be incorporated into disc-shaped devices, rods or sheetsfor under the skin implantation, spherical shapes and the like. Thoseskilled in the art would realize that the invention can be incorporatedin any shaped device for the particular application it is being usedfor.

The above described devices can be prepared by, for example:

1. Methods of preparation include: (1) Dissolution of components insolvent, evaporation of solvent, compression of matrix; (2) Mechanicalmilling of polymer, anhydride and drug or beneficial substance followedby compression; (3) Melt mixing of polymer, anhydride and drug orbeneficial substance. In all cases, after mixing, standardpharmaceutical technology is used to make the dosage form.

In order to control the rate of release of the drug or beneficialsubstance in a programable manner, one can laminate layers wherein thepolymer, acid anhydride and drug or beneficial substance in eachlaminate layer are varied in concentration or contain different speciesof each component.

Multiple anhydrides can be incorporated into the polymer to allow timevariable or geometric considerations to be achieved. Additionally, theconcentration of acid anhydride can be varied as a function of positionin the matrix.

At least enough water must be present in contact with the device toreact with the acid anhydride and the polymer to cause degradation.Water in excess of this amount will not materially effect theperformance of the invention.

In order to better describe this invention, there is follows an exampleshowing the concepts of the invention.

EXAMPLE 1

980 mg Poly(ortho ester) were dissolved in 20 ml methylene chloride. Tothe solution, acetone or methylene chloride solutions containing 20 mgof timolol maleate and 2, 3, 4 and 5 mg, respectively of maleicanhydride were added. The solvents were evaporated under reducedpressure. The residue was cut into small pieces and compressed intodiscs by a Carver Press® at 5000 lbs pressure, at 60° C. temperature andfor 5 minutes. The disc was mounted on a matched rotor, immersed in pH7.4 buffer at 37° C. and rotated at 120 rpm. The appearance of timololmaleate was followed spectrophotometrically. The drug release curve wassigmoidal with a lag phase followed by nearly zero-order release andthen a depleting phase. The release rate can be controlled by amountsand types of anhydride or anhydrides incorporated. Typical data for thisexample are shown as follows:

    ______________________________________                                        Amount of Maleic Anhydride                                                                       Rate of release of                                         incorporated in polymer                                                                          timolol maleate**                                          matrix* (%) by weight                                                                            (mg/hr)                                                    ______________________________________                                        0.2                .115                                                       0.3                .196                                                       0.4                .228                                                       0.5                .287                                                       ______________________________________                                         *HD-DETOSU/t-CDM-DETOSU (7:3 blend); 70:30 physical blend of the              following copolymers: 3,9Bis(ethylidene)2,4,8,10-tetraoxospiro                [5,5]undecane                                                                 (DETOSU) and hexane diol and DETOSUtrans-cyclohexanedimethanol.               **At 2% (w/w) Timolol Maleate                                            

Following dissolution rate testing for each composition, any blend ofpolymer, acid anhydride and drug or beneficial agent can be made toachieve the desired release characteristics for the drug or beneficialagent.

The above description and example should be considered an illustrationof this invention and not a limitation thereof.

What is claimed is:
 1. A controlled release device for the delivery ofdrugs or other biological beneficial substances which comprises:(a) Apoly(orthoester); (b) an erosion catalyzing amount up to a maximum ofabout 25 percent, by weight, based on (a), or at least one acidanhydride selected from the group consisting of a monobasic carboxylicanhydride, a cyclic dibasic carboxylic anhydride, and a polymericcarboxylic anhydride, incorporated within the matrix of saidpoly(orthoester); and (c) an effective amount up to 70 percent, byweight, based on (a) and (b), of a drug or other biological beneficialsubstance incorporated within or to be surrounded by the matix of saidpoly(orthoester),such that when said release device is exposed toaqueous environments, the matrix of said poly(orthoester) slowly erodesand said drug or beneficial substance is released in a controlledmanner.
 2. A controlled release device for the delivery of drug or otherbiological beneficial substances which comprises:(a) a poly(orthoester);(b) an erosion catalyzing amount up to a maximum of about 25 percent, byweight, based on (a), dibasic anhydride; and (c) up to 70 percent, byweight, based on (a) and (b), of a β-adrenergic blocking agent.
 3. Acontrolled drug release device of claim 1, wherein said poly(orthoester)is a polymer of Di (or a higher functionality) ketene acetals andpolyols of the formula ##STR15## wherein n is an integer substantiallygreater than 10; and wherein R₁ and R₂ are hydrogen or the same ordifferent essentially hydrocarbon groups and may be separate groups ormay form parts of a cyclic group; R is a quadrivalent organic grouping;R₃ and R₄ are hydrogen or the same or different essentially hydrocarbongroups and may be separate groups or may form parts of a cyclic group;R₅ is an essentially hydrocarbon group which is the residue of a polyolR₅ (OH)_(a) wherein a is an integer equal to two or more, such polyolbeing a single molecular species or a mixture of molecular species; andwherein such linear chain may be crosslinked with other similar chains,and wherein R may be a single quadrivalent radical attached to all theinterim acetal forming oxygen atoms, may be a spiro structure, may be anopen chain aliphatic group, or may contain a carbocyclic group andwherein additionally, R₅ may contain some mer units that are alkylene orcontain a carbocyclic group and including polymers having the repeatunits ##STR16## wherein n is an integer substantially greater than 10;wherein R₁, R₂, R₃ and R₄ are the same or different essentiallyhydrocarbon groups, R₁ and R₂ being separate groups or parts of a cyclicgroup and R₃ and R₄ being separate groups or parts of a cyclic group; R₅is an essentially hydrocarbon group which is the residue of a polyol R₅(OH)_(a) wherein a is an integer equal to two or more, such polyol beinga single molecular species or a mixture of molecular species; R₆ is avalence bond or an essentially hydrocarbon group; R₇ and R₈ are hydrogenor essentially hydrocarbon groups which may be separate groups or mayform parts of a cyclic group; and wherein such linear chains may becrosslinked to similar chains and wherein the group ##STR17## may beselected from the classic alkylene end groups containing a carbocyclicring.
 4. A controlled relese device of claim 1 wherein saidpoly(orthoester) is a polyorthocarbonate of the formula ##STR18##wherein R₁ is a multivalent hydrocarbon radical, R₂ and R₃ arehydrocarbon radicals with at least one of R₂ and R₃ are hydrocarbonradicals with at least one of R₂ or R₃ bonded to the dioxycarbon throughan oxygen linkage and n is a repeating mer unit.
 5. A controlled releasedevice of claim 1 wherein the anhydride is a monobasic carboxylicanhydride of the formula: ##STR19## wherein R, R' are hydrogen orsaturated or unsaturated hydrocarbon radicals containing up to 50 carbonatoms.
 6. A controlled release device of claim 1 wherein the anhydrideis a dibasic carboxylic anhydride of the formula: ##STR20## whereinR=(CH₂)_(n) where (n=2-4): and R' is hydrogen or a saturated hydrocarbonradical containing up to 50 carbon atoms.
 7. A controlled release deviceof claim 1 wherein the anhydride is a polymer anhydride having arepeating unit of the formula: ##STR21## wherein n is 4-50.
 8. Acontrolled drug release device of claim 1 wherein the drug or biologicalbeneficial substance is a protein drug, a desensitizing agent, avaccine, an anti-infective, an antiallergenic, a steroidalanti-inflammatory, a decongestant, a miotic, an anticholinergic, asympathomimetic, a sedative; a hypnotic, a psychic energizer, atranquilizer, an androgenic steroid, an estrogen, a progestationalagent, a humoral agent an antipyretic analgesic, an antispasmotic, anantimalarial, an antihistamine, a cardioactive agent, a non-steroidalanti-inflammatory, an antiparkinsonian agent, an antihypertensive agent,a β-adrenergic blocking agent, a nutritional agent, a herbicide, apesticide, a biocide, a fertilizer or an antifouling compound.
 9. Acontrolled release device of claim 1 composed of laminates of polymermatrices and anhydride(s).